The overall objective of the proposed research is to investigate the molecular interactions underlying the recognition and activation of the melanocortin receptor subtypes by the melanocortin peptides. This information will provide the necessary tools to design agonists and antagonists (peptidic and/or peptidomimetic) which are receptor subtype specific. These molecules can then be used to study specific biological effects associated with the melanocortin peptides, which includes activities in both the peripheral body and central nervous system. These molecules can also be designed for detection and eradication of sun- induced melanoma. The specific aims include: 1) identification of the critical structural elements of alpha-melanocyte stimulating hormone (alpha-MSH) and its receptor subtypes, hMC1R and hMC4R, required for ligand-receptor recognition, activation, and signal transduction, and 2) identification of the biological mechanism(s) leading to the prolonged- or residual, activity associated with synthetic analogues of alpha-MSH. To complete these aims, we will utilize cloned receptors transfected into eukaryotic cell lines, biological assays (binding, cAMP, and IP3) computer assisted G-protein coupled receptor modeling, peptide design and synthesis, and receptor mutagenesis.